Induction of Bim and Bid gene expression during accelerated apoptosis in severe sepsis

ABSTRACT: INTRODUCTION: In transgenic animal models of sepsis, members of the Bcl-2-family of proteins regulate lymphocyte apoptosis and survival of sepsis. This study investigates the gene regulation of pro- and anti-apoptotic members of the Bcl-2-family of proteins in patients with early stage severe sepsis. METHODS: In this prospective case-control study patients were recruited from three intensive care units in a university hospital. Sixteen patients were enrolled as soon as they fulfilled the criteria of severe sepsis. Ten critically ill but non-septic patients and eleven healthy volunteers served as controls. Blood samples were immediately obtained at inclusion. To confirm the presence of accelerated apoptosis in the patient groups, caspase-3 activation and phosphatidylserine (PS) externalization in CD4+, CD8+ and CD19+ lymphocyte subsets were assessed by flow cytometry. Specific mRNA's of Bcl-2 family members were quantified from whole blood by real-time polymerase chain reaction. To test for statistical significance, Kruskal-Wallis testing with Dunn's multiple comparison test for post hoc testing was performed. RESULTS: In all lymphocyte populations caspase-3 (p<0.05) was activated, which was reflected in an increased PS externalization (p<0.05). Accordingly, lymphocyte counts were decreased in early severe sepsis. In CD4+ T-cells (p<005) and in B-cells (p<0.001) the Bcl-2 protein was decreased in severe sepsis. Gene expression of the BH3-only Bim was massively upregulated as compared to critically ill patients (p<0.001) and 51.6 fold as compared to healthy controls (p<0.05). Bid was increased 12.9 fold compared to critically ill (p<0.001). In the group of the mitochondrial apoptosis-inducers, Bak was upregulated 5.6 fold, while the expression of Bax showed no significant variations. By contrast, the pro-survival members Bcl-2 and Bcl-xl were both downregulated in severe sepsis (p<0.001, p<0.05). CONCLUSIONS: In early severe sepsis a gene expression pattern with induction of the pro-apoptotic Bcl-2 family members Bim, Bid and Bak and a downregulation of the anti-apoptotic Bcl-2 and Bcl-xl was observed in peripheral blood. This constellation may affect cellular susceptibility to apoptosis and complex immune dysfunction in sepsis

A MIF haplotype is associated with the outcome of patients with severe sepsis: a case control study

<p>Abstract</p> <p>Background</p> <p>Macrophage migration inhibitory factor (MIF) plays an important regulatory role in sepsis. In the promoter region a C/G single nucleotide polymorphism (SNP) at position -173 (rs755622) and a CATT_5-8microsatellite at position -794 are related to modified promoter activity. The purpose of the study was to analyze their association with the incidence and outcome of severe sepsis.</p> <p>Methods</p> <p>Genotype distributions and allele frequencies in 169 patients with severe sepsis, 94 healthy blood donors and 183 postoperative patients without signs of infection or inflammation were analyzed by real time PCR and Sequence analysis. All included individuals were Caucasians.</p> <p>Results</p> <p>Genotype distribution and allele frequencies of severe sepsis patients were comparable to both control groups. However, the genotype and allele frequencies of both polymorphisms were associated significantly with the outcome of severe sepsis. The highest risk of dying from severe sepsis was detectable in patients carrying a haplotype with the alleles -173 C and CATT₇(p = 0.0005, fisher exact test, RR = 1,806, CI: 1.337 to 2.439).</p> <p>Conclusion</p> <p>The haplotype with the combination of the -173 C allele and the -794 CATT₇allele may not serve as a marker for susceptibility to sepsis, but may help identify septic patients at risk of dying.</p

Rapid Qualitative Urinary Tract Infection Pathogen Identification by SeptiFast® Real-Time PCR

Background Urinary tract infections (UTI) are frequent in outpatients. Fast pathogen identification is mandatory for shortening the time of discomfort and preventing serious complications. Urine culture needs up to 48 hours until pathogen identification. Consequently, the initial antibiotic regimen is empirical. Aim To evaluate the feasibility of qualitative urine pathogen identification by a commercially available real-time PCR blood pathogen test (SeptiFast®) and to compare the results with dipslide and microbiological culture. Design of study Pilot study with prospectively collected urine samples. Setting University hospital. Methods 82 prospectively collected urine samples from 81 patients with suspected UTI were included. Dipslide urine culture was followed by microbiological pathogen identification in dipslide positive samples. In parallel, qualitative DNA based pathogen identification (SeptiFast®) was performed in all samples. Results 61 samples were SeptiFast® positive, whereas 67 samples were dipslide culture positive. The inter-methodological concordance of positive and negative findings in the gram+, gram- and fungi sector was 371/410 (90%), 477/492 (97%) and 238/246 (97%), respectively. Sensitivity and specificity of the SeptiFast® test for the detection of an infection was 0.82 and 0.60, respectively. SeptiFast® pathogen identifications were available at least 43 hours prior to culture results. Conclusion The SeptiFast® platform identified bacterial DNA in urine specimens considerably faster compared to conventional culture. For UTI diagnosis sensitivity and specificity is limited by its present qualitative setup which does not allow pathogen quantification. Future quantitative assays may hold promise for PCR based UTI pathogen identification as a supplementation of conventional culture methods

Clinical Characteristics of Inpatients with Childhood vs. Adolescent Anorexia Nervosa

We aimed to compare the clinical data at first presentation to inpatient treatment of children (<14 years) vs. adolescents (≥14 years) with anorexia nervosa (AN), focusing on duration of illness before hospital admission and body mass index (BMI) at admission and discharge, proven predictors of the outcomes of adolescent AN. Clinical data at first admission and at discharge in 289 inpatients with AN (children: n = 72; adolescents: n = 217) from a German multicenter, web-based registry for consecutively enrolled patients with childhood and adolescent AN were analyzed. Inclusion criteria were a maximum age of 18 years, first inpatient treatment due to AN, and a BMI <10th BMI percentile at admission. Compared to adolescents, children with AN had a shorter duration of illness before admission (median: 6.0 months vs. 8.0 months, p = 0.004) and higher BMI percentiles at admission (median: 0.7 vs. 0.2, p = 0.004) as well as at discharge (median: 19.3 vs. 15.1, p = 0.011). Thus, in our study, children with AN exhibited clinical characteristics that have been associated with better outcomes, including higher admission and discharge BMI percentile. Future studies should examine whether these factors are actually associated with positive long-term outcomes in children

Premorbid body weight predicts weight loss in both anorexia nervosa and atypical anorexia nervosa: Further support for a single underlying disorder.

OBJECTIVE For adolescents, DSM-5 differentiates anorexia nervosa (AN) and atypical AN with the 5th BMI-centile-for-age. We hypothesized that the diagnostic weight cut-off yields (i) lower weight loss in atypical AN and (ii) discrepant premorbid BMI distributions between the two disorders. Prior studies demonstrate that premorbid BMI predicts admission BMI and weight loss in patients with AN. We explore these relationships in atypical AN. METHOD Based on admission BMI-centile < or ≥5th, participants included 411 female adolescent inpatients with AN and 49 with atypical AN from our registry study. Regression analysis and t-tests statistically addressed our hypotheses and exploratory correlation analyses compared interrelationships between weight loss, admission BMI, and premorbid BMI in both disorders. RESULTS Weight loss in atypical AN was 5.6 kg lower than in AN upon adjustment for admission age, admission height, premorbid weight and duration of illness. Premorbid BMI-standard deviation scores differed by almost one between both disorders. Premorbid BMI and weight loss were strongly correlated in both AN and atypical AN. DISCUSSION Whereas the weight cut-off induces discrepancies in premorbid weight and adjusted weight loss, AN and atypical AN overall share strong weight-specific interrelationships that merit etiological consideration. Epidemiological and genetic associations between AN and low body weight may reflect a skewed premorbid BMI distribution. In combination with prior findings for similar psychological and medical characteristics in AN and atypical AN, our findings support a homogenous illness conceptualization. We propose that diagnostic subcategorization based on premorbid BMI, rather than admission BMI, may improve clinical validity. PUBLIC SIGNIFICANCE Because body weights of patients with AN must drop below the 5th BMI-centile per DSM-5, they will inherently require greater weight loss than their counterparts with atypical AN of the same sex, age, height and premorbid weight. Indeed, patients with atypical AN had a 5.6 kg lower weight loss after controlling for these variables. In comparison to the reference population, we found a lower and higher mean premorbid weight in patients with AN and atypical AN, respectively. Considering previous psychological and medical comparisons showing little differences between AN and atypical AN, we view a single disorder as the most parsimonious explanation. Etiological models need to particularly account for the strong relationship between weight loss and premorbid body weight

The impact of the COVID-19 pandemic on administrative eating disorder prevalence in the outpatient sector and on severity of anorexia nervosa.

The COVID-19 pandemic appears to have had a considerable impact on the mental health of children and adolescents, particularly regarding eating disorders. However, it remains unclear whether the pandemic affected only the frequency or also the severity of eating disorders. We examined potential pandemic-related changes in the administrative prevalence of eating disorders in the outpatient sector compared with other mental disorders using German statutory health insurance data for the age group 10 to 16 years. We also examined disorder severity of anorexia nervosa using data from the multicenter German Registry of Children and Adolescents with Anorexia Nervosa in the same age group. Our results showed a marked increase in the administrative prevalence of eating disorders (based on documented diagnoses) in the outpatient sector among girls but not among boys. A similar pattern was found for internalizing disorders, whereas the administrative prevalences of externalizing disorders decreased. Regarding the severity of anorexia nervosa among inpatients, we found no pandemic-related changes in body mass index standard deviation score at admission, body weight loss before admission, psychiatric comorbidities and psychopharmacological medication. Given the administrative prevalence increase in the outpatient sector, the lack of impact of the pandemic on the inpatient sector may also be partly due to a shift in healthcare utilization towards outpatient services during the pandemic. Thus, the higher number of children and adolescents requiring specialized and timely outpatient care may be a major concern under pandemic conditions

A Proposal for a Three Detector Short-Baseline Neutrino Oscillation Program in the Fermilab Booster Neutrino Beam

A Short-Baseline Neutrino (SBN) physics program of three LAr-TPC detectors located along the Booster Neutrino Beam (BNB) at Fermilab is presented. This new SBN Program will deliver a rich and compelling physics opportunity, including the ability to resolve a class of experimental anomalies in neutrino physics and to perform the most sensitive search to date for sterile neutrinos at the eV mass-scale through both appearance and disappearance oscillation channels. Using data sets of 6.6e20 protons on target (P.O.T.) in the LAr1-ND and ICARUS T600 detectors plus 13.2e20 P.O.T. in the MicroBooNE detector, we estimate that a search for muon neutrino to electron neutrino appearance can be performed with ~5 sigma sensitivity for the LSND allowed (99% C.L.) parameter region. In this proposal for the SBN Program, we describe the physics analysis, the conceptual design of the LAr1-ND detector, the design and refurbishment of the T600 detector, the necessary infrastructure required to execute the program, and a possible reconfiguration of the BNB target and horn system to improve its performance for oscillation searches.Comment: 209 pages, 129 figure

Search for Charginos with a Small Mass Difference with the Lightest Supersymmetric Particle at \sqrt{s} = 189 GeV

A search for charginos nearly mass-degenerate with the lightest supersymmetric particle is performed using the 176 pb^-1 of data collected at 189 GeV in 1998 with the L3 detector. Mass differences between the chargino and the lightest supersymmetric particle below 4 GeV are considered. The presence of a high transverse momentum photon is required to single out the signal from the photon-photon interaction background. No evidence for charginos is found and upper limits on the cross section for chargino pair production are set. For the first time, in the case of heavy scalar leptons, chargino mass limits are obtained for any \tilde{\chi}^{+-}_1 - \tilde{\chi}^0_1 mass difference

Search for Branons at LEP

We search, in the context of extra-dimension scenarios, for the possible existence of brane fluctuations, called branons. Events with a single photon or a single Z-boson and missing energy and momentum collected with the L3 detector in e^+ e^- collisions at centre-of-mass energies sqrt{s}=189-209$ GeV are analysed. No excess over the Standard Model expectations is found and a lower limit at 95% confidence level of 103 GeV is derived for the mass of branons, for a scenario with small brane tensions. Alternatively, under the assumption of a light branon, brane tensions below 180 GeV are excluded

Measurement of Exclusive rho^0 rho^0 Production in Two-Photon Collisions at High Q^2 at LEP

Exclusive rho rho production in two-photon collisions involving a single highly virtual photon is studied with data collected at LEP at centre-of-mass energies 89GeV < \sqrt{s} < 209GeV with a total integrated luminosity of 854.7pb^-1 The cross section of the process gamma gamma^* -> rho rho is determined as a function of the photon virtuality, Q^2 and the two-photon centre-of-mass energy, Wgg, in the kinematic region: 1.2GeV^2 < Q^2 < 30GeV^2 and 1.1GeV < Wgg < 3GeV